A Phase 3 study to evaluate whether macitentan 75 mg is an effective and safe treatment for patients with inoperable or persistent chronic thromboembolic pulmonary hypertension.
- Conditions
- Chronic thromboembolic pulmonary hypertensionMedDRA version: 21.1Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2019-004131-24-DK
- Lead Sponsor
- ACTELION Pharmaceuticals Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 230
• Male or female =18 (or the legal age of consent in the jurisdiction in which the study is taking place) and =80 years of age.
• CTEPH (WHO Group 4) fulfilling one of the following criteria:
a. Inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the adjudication committee (AC), and diagnosed based on
• At least 2 of the following assessments in the 14 month-period prior to Randomization: Ventilation / Perfusion (V/Q) scan, pulmonary angiography (PA), computed tomography pulmonary angiogram (CTPA), magnetic resonance angiography (MRA).
- RHC at least 12 weeks after full anticoagulation showing the following (at Screening or in the 24 week period prior to Randomization): mPAP > 20 mmHg, PAWP =15 mmHg and PVR =240 dyn·sec/cm5.
b. Persistent/recurrent CTEPH after BPA, and deemed inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the AC, diagnosed based on:
• At least one of the following assessments performed after the latest BPA in the 14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA
• RHC at least 12 weeks after BPA and full anticoagulation showing the following (at Screening or in the 24-week period prior to Randomization): mPAP > 20 mmHg, PAWP =15 mmHg and PVR=240 dyn·sec/cm5.
c. Persistent/recurrent CTEPH after PEA (including PEA followed by BPA), diagnosed based on:
• At least one of the following assessments performed after the PEA (and latest BPA following PEA, if applicable) in the 14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA.
• RHC performed at least 12 weeks after PEA (or latest BPA, if applicable) and full anticoagulationa showing the following (at Screening or in the 24 week period prior to Randomization): mPAP > 20 mmHg, PAWP =15 mmHg and PVR=240 dyn·sec/cm5.
• 6MWD = 100 m AND = 450 m, documented by an eligibility and a baseline 6MWT. The baseline 6MWD must not differ by more than 15% from the eligibility test.
• WHO FC =II.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 80
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 150
• Acute pulmonary embolism within 3 months prior to or during Screening.
• Planned BPA during the fixed duration part of the double-blind period
• Significant obstructive and restrictive lung disease.
• Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (eg, intermittent claudication).
• Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the fixed duration part of the study.
• Decompensated cardiac failure if not under close supervision.
• Known and documented life-threatening cardiac arrhythmias.
• Acute myocardial infarction within 6 months prior to, or during Screening.
• Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening.
• Known or suspicion of pulmonary veno-occlusive disease (PVOD).
• Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or investigational treatment within 90 days prior to Randomization.
• Change in dose or initiation of PDE-5 inhibitors, oral inhaled or SC prostacyclins / prostacyclin analogues, prostacyclin receptor agonists (or riociguat, within 90 days prior to Randomization, or anticipated during the fixed duration part of the DB period.
• Hypotension, ie, systolic blood pressure (SBP) <90 mmHg or diastolic blood pressure (DBP) <50 mmHg at Screening.
• Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening.
• Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history.
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =1.5 the upper limit of normal (ULN) at Screening.
• Hemoglobin =100 g/L (<10 g/dL) at Screening.
• Treatment with strong CYP3A4 inhibitors, (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or moderate dual CYP3A4/CYP2C9 inhibitors (eg, fluconazole, amiodarone) or coadministration of a combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, piperine), within 30 days prior to Randomization.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).<br>;Secondary Objective: • To evaluate the effect of macitentan 75 mg versus placebo on time to clinical worsening up to EODBT.<br>• To evaluate the effect of macitentan 75 mg versus placebo on WHO FC at Week 28.<br>• To evaluate the effect of macitentan 75 mg versus placebo on quality of life at Week 28.<br>• To evaluate the effect of macitentan 75 mg versus placebo on daily physical activity.;Primary end point(s): Change from baseline to Week 28 in exercise capacity (6-minute walk distance [6MWD], as measured by the 6-minute Walk Test [6MWT]).<br>;Timepoint(s) of evaluation of this end point: From baseline to Week 28.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Time to first Clinical Event Committee (CEC) confirmed clinical worsening up to EODBT.<br>• Improvement in WHO FC from baseline to Week 28.<br>• Change from baseline to Week 28 in<br> • Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®)<br> - Cardiopulmonary symptom domain score<br> - Cardiovascular symptom domain score<br>• Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L©) utility score.<br>• Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity.;Timepoint(s) of evaluation of this end point: Week 28 and up to End-of-double-blind treatment (EODBT).